The present invention relates to novel 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-c arboxylic acid.sesquihydrate, processes for the preparation thereof, a pharmaceutical composition containing it and also its use.
1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-ca rboxylic acid (this compound is sometimes referred to as "AT-2266" hereinafter) is expressed by the following structural formula. ##STR1##
Methods for synthesizing the AT-2266 and the usefulness of the AT-2266 as a chemotherapeutic agent were already disclosed in the specification of European Laid-Open Patent Publication No. 9425, Apr. 2, 1980, Bulletin Number 80/7. The European Patent Specification generally describes that the AT-2266, etc. may exist in the form of a hydrate, but fails to give any specific description about the AT-2266 hydrate.
British Laid-Open Patent Publication No. 2034698 A discloses AT-2266 and its hydrates and acid addition salts. No specific statement is made, however, about methods for producing AT-2266 and its hydrates.
The present inventors have continued to study the physical and chemical properties of the AT-2266 and found that AT-2266 can exist in the form of a trihydrate as well as in anhydrous form. Specifically, they have found that contacting of anhydrous AT-2266 (this compound is sometimes referred to as "anhydrate" hereinafter) with water at room temperature results in the ready conversion of the anhydrate into AT-2266.trihydrate (this compound is sometimes referred to as "trihydrate" hereinafter) and the trihydrate is converted back into the anhydrous form by drying it. Moreover, both the anhydrate and the trihydrate have been found to be unstable to light.
Hence, in the preparation of these compounds and pharmaceutical preparations, such as tablets, containing these compounds, the operations must be carried out under shielding of light with sufficient attention to absorption or desorption of water of crystallization. During storage and handling, too, these products must be protected from light, heat and/or atmospheric moisture. More specifically, a room in which to handle the anhydrate must be kept at the lowest possible humidity, and conversely, a room in which to handle the trihydrate must be kept at the lowest possible temperature and the highest possible humidity. Moreover, these rooms should be as dark as possible, and preferably darkrooms. Unless all of these conditions are provided, these compounds or preparations containing these compounds would change in weight, and/or turn yellow, and thus would not serve for practical purposes and would lose their commercial value.
In particular, difficulty is encountered in the production of pharmaceutical preparations such as tablets which contain the trihydrate because all of the steps of production must be carried out under conditions which do not cause the loss of its water of crystallization. For example, even when the trihydrate is used in preparing tablets, its water of crystallization is lost during a drying step usually carried out at 40.degree.-50.degree. C., and tablets containing only the trihydrate cannot be obtained. The resulting tablets contain either a mixture of the anhydrate and the trihydrate or only the anhydrate.
Accordingly, these compounds still have great defects.